The transcriptional function of many nuclear receptors (NRs) is regulated by ligand-dependent recruitment of coactivators to the carboxyl-terminal ligand-binding domain (Aranda, A., and Pascual, A. (2001) Physiol. Rev. 81:1269-1304; Rosenfeld, M. G. and Glass, C. K. (2001) J. Biol. Chem. 276:36865-36868). A number of coactivators, including the p160 family, p300/CBP and P/CAF, contain intrinsic histone acetyl transferase activity and regulate transcription by modulating histone acetylation (Aranda and Pascual (2001) supra). Other coactivators, consisting of heterogeneous proteins with little sequence homology, modulate transcription by acting as protein docking interfaces that recruit histone acetyl transferase-containing complexes or associate with basal transcription factors such as RNA polymerase II holoenzyme (Freedman, L. P. (1999) Cell 97:5-8). The interaction between NRs and many coactivators requires a conserved LXXLL motif (L is leucine and X is any amino acid), which is believed to form hydrophobic contacts with the receptors (Nolte, R. T. et al. (1998) Nature 395:137-143; Westin, S. et al. (1998) Nature 395:199-202).
PGC-1 was initially identified as a PPARγ-interacting protein from a brown adipose tissue (BAT) library and was subsequently found to associate with an array of NRs and transcription factors (Puigserver, P. et al. (1998) Cell 92:829-839; Wu, Z. et al. (1999) Cell 98:115-124; Vega, R. B. et al. (2000) Mol. Cell. Biol. 20:1868-1876; Michael, L. F. et al. (2001) Proc. Natl. Acad. Sci. USA 98:3820-3825). Importantly, PGC-1 has been shown to coordinately regulate the program of mitochondrial biogenesis and adaptive thermogenesis in BAT and skeletal muscle, mainly through the coactivation of PPARs and nuclear respiratory factor 1 (NRF1), a nuclear transcription factor that regulates the expression of many mitochondrial genes (Puigserver et al. (1998) supra; Wu et al. (1999) supra). In transgenic mice, PGC-1 increases mitochondrial biogenesis and β-oxidation of fatty acids in the heart, likely through augmentation of PPARα and NRF1 transcriptional activity (Lehman, J. J. et al. (2000) J. Clin. Invest. 106:847-856). Recently, PGC-1 expression was found to be elevated in fasted liver and several models of type-1 and type-2 diabetes; in addition, PGC-1 can directly control the activation of hepatic gluconeogenesis (Yoon, J. C. et al. (2001) Nature 413:131-138; Herzig, S. et al. (2001) Nature 413:179-183).